T lymphocytes modified with chimeric-antigen receptors (CARs) bearing the CD3-zeta signaling domain exhibit moderate levels of target tumor cytolysis and low amounts of cytokine production. The incorporation of costimulatory signaling domains, usually that of CD28 or 4-1BB, into second-generation CARs significantly increases target cell killing and cytokine production. It has been shown that ligation of the natural CD2 molecule resulted in quantitative and qualitative differences compared to TCR-induced calcium signal transduction. Recent reports demonstrated that ligation of the endogenous CD2 receptor significantly increases IL-2 produced from first-generation CAR-T cells.
Current data indicates that CAR T cells need to engraft and survive in patients who have clinically beneficial tumor responses (Porter et al., 2011, N Engl J Med, 365:725-33). However, activation-induced T cell death can occur when the threshold for too much signal transduction is reached (Viola et al., 1996, Science. 273(5271):104-6; Ren-Heidenreich et al., 2002, Cancer Immunol Immunother, 2002:417-23; Bachmann et al., 1996, Eur J Immunol, 26(9):2017-22; Ren-Heidenreich et al., 2001, Curr Gene Ther, 1(3):253-5; Borthwick et al., 1996, Immunology, (4):508-15).
Thus, there is an urgent need in the art for compositions of CARs that regulate T cell responses to enhance CAR T cell survival and provide a beneficial environment for anti-tumor activity. The present invention addresses this need.